The Minnesota Twin Family Study (MTFS) seeks to identify genetic and environmental influences on the development of substance abuse (SA) and associated psychological disorders. An epidemiologically based sample of approximately 670 male pre-adolescent and adolescent twin pairs and their parents (a total of 2680 individuals) are undergoing a one-day comprehensive assessment that includes (1) mental health, (2) substance use and abuse history, (3) psychophysiological markers of risk, (4) personality/interests/social adjustment, and (5) environmental moderators of risk. Two cohorts are being assessed: twins are first assessed either when they are 11 years old, just prior to their initial experimentation with alcohol and other drugs, or at age 17, prior to the establishment of adult drinking and drug use patterns and the onset of adult psychological disorders. The sample is selected in such a way that approximately 40% of the twins have one or both biological parents with a DSM-III-R diagnosis of Substance Dependence (i.e., High Risk), 20% of twins have one or both biological parents with a DSM-II-R diagnosis of Substance Abuse but not Dependence (i.e., Medium Risk), 10% have one or both biological parents with a psychiatric disorder but not a SA diagnosis (i.e., Psychiatric Controls), and 30% of twins have both biological parents with no psychiatric or SA diagnosis (i.e., Controls). The project is designed as a prospective study of the etiology of psychoactive SA and related disorders. We are requesting funding to complete the last year of intake recruitment, to continue our yearly telephone/mail follow-up assessment, and to reassess the sample in our laboratory at 3-year intervals as the twins progress through the major life changes that characterize adolescence and early adulthood. The focus of analysis of the cross-sectional data will be on the high-risk aspects of the design as well as on understanding adolescent drug use and abuse from a behavioral genetic perspective. That is, we will seek to (1) identify early markers of risk, (2) characterize the genetic and environmental determinants of individual differences in these markers, and (3) identify interactions between biological risk status and environmental factors. Our longitudinal analyses will focus on how genetic and environmental factors mediate the development of substance use and abuse behavior, with special emphasis on how changes in the gene- environment interaction influence the developmental course of SA and related disorders. Additionally, our study of male adolescent twins parallels a proposed study of 600 female adolescent twins and their parents. This will provide us with the unique opportunity to identify sex differences in the origins of substance use and related disorders and determine whether and how those sex differences interact with genetic and environmental markers of risk.